Prenatal iron supplements

ABSTRACT

Multimineral dietary supplement compositions of enhanced iron bioavailability are provided by the use of controlled quantities of oxides and carbonates of calcium and magnesium.

BACKGROUND OF THE INVENTION

Mineral and vitamin compositions are commonly taken as dietary aidseither as therapeutic preparations directed to a specific medicalproblem or as general nutritional supplements.

Iron deficiency anemias have been conventionally treated with a widevariety of compounds including elementary iron, ferrous compounds,ferric compounds and iron complexes. One of the most common forms ofiron-deficiency anemia is that associated with pregnancy.

In treating iron-deficiency anemia, it is important that thebioavailability of the iron be maximized for a given iron content.Simply increasing the iron content in a unit dosage in an effort toachieve the required levels of iron absorption can cause constipationand other undesired G.I. side effects without achieving the anticipatedlevel of absorption due to interference in the iron's absorption fromother components contained in the dietary supplement composition.

SUMMARY OF THE INVENTION

This invention relates to multimineral, dietary supplement compositionsfor the treatment of iron deficiency anemia which provide enhancedlevels of iron bioavailability. This is achieved by the use ofcontrolled levels of oxides and carbonates of co-administered minerals,such as calcium and magnesium. The compositions are especially useful inprenatal therapy.

DETAILED DESCRIPTION OF THE INVENTION

Elemental iron and a wide variety of iron compounds have beenconventionally used as hematinics in the therapeutic treatment ofanemias and as nutritional supplements to insure satisfaction of thebodies minimum daily recommended allowance of iron. Commonly, suchagents are administered in combinations of a variety of minerals and/orvitamins for which minimum recommended daily allowances have beenestablished.

One of the most common causes of iron-deficiency anemia is thatassociated with pregnancy. During pregnancy and lactation, it is commonto supplement the body's enhanced need of iron, calcium, magnesium andother minerals as well as its enhanced requirements of vitamins via aprenatal multivitamin, multimineral dietary supplement.

It has now been found that the bioavailability of an iron supplement canbe enhanced by controlling the levels of the oxides and carbonates ofminerals such as calcium and magnesium used in the mineral supplementcompositions.

Iron-deficiency anemias can be treated by oral administration of solubleiron salts in the ferrous or ferric state, e.g., ferrous chloride,ferrous fumarate, ferrous gluconate and ferric ammonium citrate as wellas in the form of natural and synthetic complexes of iron and elementaliron.

Recommended minimum daily requirements of iron and a variety of otherminerals such as calcium, potassium, magnesium, copper and zinc havelong been established together with minimum daily requirements of avariety of vitamins such as A, D, E, C, B₁, B₂, B₆ and B₁₂. Suchminerals and vitamins are commonly prescribed in combination as a dailydietary supplement as well as for the therapeutic treatment of specificmedical problems associated with specific deficiencies.

It has now been found that the combined quantities of oxides andcarbonates of the minerals coadministered with the iron play asubstantial role in the bioavailability of the iron component and thatthe control of the upper limit of the combined quantities enhances theabsorption of the iron supplement. Calcium and magnesium presentprinciple problems in that magnesium is commonly employed in the form ofmagnesium oxide and calcium is commonly employed in the form of calciumcarbonate.

While calcium and magnesium are almost always present in multi-mineralcompositions, especially in the case of prenatal compositions, they areless necessary from a dietary supplement point of view in that adequatequantities of each can be maintained through proper diet. In contrast,however, prenatal supplementation of iron is very important.

Accordingly, in the compositions of the present invention, thequantities of calcium and magnesium can be reduced to zero. Thecoadministered minerals such as calcium and magnesium when present intheir oxide and carbonate form should not exceed 300 mg and 75 mg perunit dosage respectively. These quantities and those appearing below arebased upon the elemental metal rather than the oxide or carbonate saltsor other salts used unless otherwise indicated. More preferredcompositions contain calcium carbonate with calcium at the 250 mg levelor less per unit dosage and magnesium oxide with the magnesium presentat the 25 mg level or less per unit dosage.

It is preferred to administer the compositions of the present inventionin the form of tablets; however, any conventional form of orallyadministering vitamins can be used. Conventionally used iron compoundsand formulation methods as well as pharmaceutically acceptableformulation aids and adjuvants are well known in the patent andtechnical literature, e.g., U.S. Pat. No. 2,823,167 to H. L. Newmark;U.S. Pat. No. 2,816,854 to R. H. Gross and Remington's Practice ofPharmacy, Martin and Cook (1961) see page 46 et seq. for hematopoietics.

It will also be understood that the invention is not limited to thematerials, proportions, methods and the like specifically described andexemplified below, which can be modified without departing from thescope of the invention.

EXAMPLE 1

A film coated tablet for use as a prenatal multi-vitamin-mineralsupplement with enhanced iron bioavailability was prepared with eachtablet containing about the International Units (I.U.) or mg. ofingredients listed below. The percentage of U.S. Recommended DailyAllowance of the components for pregnant or lactating women is listed inparentheses thereafter. The conventional formula which it replaces isset forth for purposes of comparison:

    ______________________________________                                                                   Conven-                                                               New For-                                                                              tional For-                                                           mulation                                                                              mulation                                                              MB      MO                                                 ______________________________________                                        Vitamin A Acetate    8,000  I.U.   8,000                                                                              I.U.                                  Vitamin D            400    I.U.   400  I.U.                                  Vitamin E            30     I.U.   30   I.U.                                  (as dl-Alpha Tocopheryl Acetate)                                              Vitamin C            100    mg     120  mg                                    (Ascorbic Acid)                                                               Folic Acid           1      mg     1    mg                                    Thiamine             3      mg     3    mg                                    (as Thiamine Mononitrate Vitamin B.sub.1)                                     Riboflavin           3.4    mg     3.4  mg                                    (Vitamin B.sub.2)                                                             Vitamin B.sub.6      4      mg     4    mg                                    (as Pyridoxine Hydrochloride)                                                 Niacinamide          20     mg     20   mg                                    Vitamin B.sub.12     12     mcg    12   mcg                                   (Cyanocobalamin)                                                              Calcium              250    mg     350  mg                                    (as Calcium Carbonate)                                                        Iodine               0.3    mg     0.3  mg                                    (as Potassium Iodide)                                                         Elemental Iron       60     mg     [60  mg]                                   (as Ferrous Fumarate)                                                         Magnesium            25     mg     [100 mg]                                   (as Magnesium Oxide)                                                          Copper               2      mg     2    mg                                    (as Cupric Oxide)                                                             Zinc                 25     mg     15   mg                                    (as Zinc Sulfate)                                                             Docusate Sodium USP  50     mg     50   mg                                    (DSS)                                                                         ______________________________________                                    

The absorption of iron was established by collection of venous bloodsamples collected by hypodermic syringe and clotted at room temperaturefor one hour in silicone coated glass tubes. The tubes were centrifugedat 4,000 g for 30 minutes at 4° C. to isolate the serum which is removedand stored at -20° C. The serum samples were assayed for serum iron viaspectrophotometry using ferrozine reagent.

In addition to testing the above formulations for iron absorption,various other commercial formulations designated as ST, MO, NL and NFare included for comparative purposes, together with a slurry of ferrousfumarate per se and ferrous fumarate taken with various combinations ofcalcium carbonate, calcium sulfate, magnesium oxide and magnesiumhydroxide. The "New Formulation" above is referred to as MB. Aformulation identical to MB except with regard to the calcium carbonatelevel was prepared and labeled MA. Formulation MA contains 350 mg ofcalcium carbonate. The Conventional Formulation is referred to as MObelow.

The tests were conducted in healthy menstruating female volunteers 21 to45 years of age having normal hemoglobin and hematocrit valves. Thesubjects fasted overnight. Fifteen to 24 subjects were used in eachstudy. Each study was conducted as a randomized crossover trial with thecomposition being administered at 8 a.m. at 3 to 4 day intervals. Bloodwas first taken in the fasting state. Then the preparation wasadministered using 50 ml of deionized water and the subjects remainedfasting until the final blood sample was obtained. Serum iron levelswere assayed in duplicate on a blind basis.

Changes in serum iron concentration were measured in 24 subjects afteringestion of 50 ml of deionized water alone showed a mean increase inserum iron concentration of 2.3 ug per 100 ml per hour. All valves werecorrected using this valve for diurnal variation. Values for ironabsorption were calculated from the increases in serum ironconcentration measured 2 to 6 hours after iron ingestion.

As a control, serum iron concentration was also measured after oraladministration of 65 mg of elmental iron given in the form of a ferrousfumarate slurry. A valve of 8.0 mg for mean iron absorption wascalculated for the iron administered alone. Since the mean valves forthe change in serum iron concentration were very similar at 2, 4 and 6hours after ingestion, all subsequent studies of iron absorption wereperformed using only fasting and 3 hour post ingestion serum ironconcentrations.

The results of these studies are shown in Table I below. In each case,the quantities of mineral stated are on the basis of the elemental metalas opposed to the weight of the entire salt.

                                      TABLE I                                     __________________________________________________________________________    SUMMARY OF IRON FORMULATIONS AND IRON ABSORPTION IN VARIOUS EXPERIMENTS                      Form and amount of calcium                                                    and magnesium present or (added)                                                                     Calculated mean values                            Amount                                                                             at the time of ingestion                                                                             for iron absorption in                            of iron                                                                            Calcium                                                                            Calcium                                                                             Magnesium                                                                           Magnesium                                                                           various studies                         Iron      Ingested                                                                           sulfate                                                                            carbonate                                                                           oxide hydroxide                                                                           Study I                                                                           Study II                                                                           Study III                                                                          Study                                                                              Average              Preparation                                                                             (mg) (mg) (mg)  (mg)  (mg)  (mg)                                                                              (mg) (mg) (mg) (mg)                 __________________________________________________________________________    Ferrous fumarate                                                                        65   --   --    --    --    8.0 9.0  --   7.3  8.1                  ST        65   200  --    100   --    2.0 --   1.3  2.2  1.8                  MO        60   --   350   100   --    2.8 --   --   --                        Ferrous fumarate                                                                        65   (200)                                                                              --    --    --    --  9.5  --   --                        Ferrous fumarate                                                                        65   --   (350) --    --    --  6.8  --   --                        Ferrous fumarate                                                                        65   --   --    (100) --    --  6.6  --   --                        Ferrous fumarate                                                                        65   (200)                                                                              --    (100) --    --  6.2  --   --                        Ferrous fumarate                                                                        65   --   (350) (100) --    --  4.3  --   --                        New Formulation A                                                                       60   --   350    25   --    --  --   3.0  --                        New Formulation B                                                                       60   --   250    25   --    --  --   5.0  4.1  4.5                  NL        60   --   200   --    100   --  --   --   2.4                       NF        65   --   350   100   --    --  --   --   3.0                       __________________________________________________________________________

The results reported in Table I above are graphically depicted in FIGS.1-4. In each case, the bar graphs show the mean values of the pointsobserved.

FIG. 1 shows the results of Study I using ferrous fumarate alone (Fe)and commercial product ST and conventional formulation MO with serumiron concentrations measured at 2, 4 and 6 hours after ingestion. Thisstudy involved 15 female subjects of child bearing age.

FIG. 2 shows the results of Study II establishing the effects on ironabsorption of calcium sulfate, calcium carbonate, magnesium oxide andcombination of these calcium and magnesium salts. The additiveinhibitory effects on iron absorption due to calcium carbonate andmagnesium oxide can be seen therefrom. Plaster of paris does not seem tobe inhibitory perhaps due to the formation of an inert state. Again, 15females of child bearing age were studied using ferrous fumarate aloneand in combinations of calcium sulfate (CS), calcium carbonate (CC) andmagnesium oxide (MX). The study involved 15 females of child bearing agewith data obtained three hours after oral ingestion.

FIG. 3 shows the changes in serum iron concentration in 15 females ofchild bearing age from Study III using commercial products ST and newformulations MA and MB. The data were obtained 3 hours after oralingestion.

In new formulation MA the level of calcium carbonate was maintained at350 mg of elemental calcium and the level of elemental magnesium in theform of magnesium oxide was reduced from 100 mg to 25 mg. In newformulation MB the level of calcium in the form of calcium carbonate wasreduced to 250 mg and the amount of elemental magnesium in the form ofmagnesium oxide was reduced to 25 mg.

The level of mean iron absorption in new formulation MA was increased to3.0 mg from 1.3 mg in the commercial ST product. In new formulation MBthe level was increased to 5.0 mg, dramatically showing the depressanteffects of the calcium carbonate and magnesium oxide mineral componentson the bioavailability of the iron supplement.

FIG. 4 shows the results from Study IV. The graph contrasts the resultsachieved with new formulation MB in comparison to three commercialformulations ST, NL and NF with a ferrous fumarate control (Fe).

Again, the composition of the present invention afforded an iron levelof 4.1 mg versus absorption levels of 2.2 mg; 2.4 mg; and 3.0 mg ofabsorbed iron for the three commercial preparations respectfully.

I claim:
 1. A method of enhancing the absorption of iron inmultimineral, iron-supplement preparations comprising the use of limitedquantities of oxides and carbonates of calcium and magnesiumadministered in said preparations to not more than 300 mg and 75 mgrespectively per unit dosage based upon the weight of elemental calciumand magnesium in said oxide and carbonate salts.
 2. A method accordingto claim 1 wherein the calcium is administered in the form of calciumcarbonate.
 3. A method according to claim 2 wherein the calciumcarbonate is present in from 150 mg to 275 mg per unit dosage based onthe weight of calcium in said calcium carbonate and the iron supplementis selected from the group consisting of ferrous fumarate, ferrousgluconate and ferrous sulfate.
 4. A method according to claim 3 whereinthe preparation contains from about 45 mg to about 65 mg of ironsupplement based on elemental iron.
 5. A method according to claim 1wherein the magnesium is in the form of magnesium oxide.
 6. A methodaccording to claim 5 wherein the magnesium oxide is present in from 15mg to 50 mg per unit dosage based on the weight of magnesium in saidmagnesium oxide and the iron supplement is selected from the groupconsisting of ferrous fumarate, ferrous gluconate and ferrous sulfate.7. A method according to claim 6 wherein the preparation contains fromabout 45 to about 65 mg of iron supplement based on elemental iron.
 8. Amethod according to claim 1 wherein said preparation is a prenatal,multivitamin, multimineral composition in solid unit dosage formcontaining sufficient international units of the essential vitamins andminerals to provide 100% of the minimum recommended daily allowance withthe exception of calcium and magnesium which are present as calciumcarbonate and magnesium oxide in amounts of not greater than about 250mg per unit dose and about 25 mg per unit dose respectively.
 9. Amultimineral, iron-supplement preparation providing enhanced absorptionof iron from said multimineral preparation comprising in combinationwith said mineral and iron supplements, oxides and carbonates of calciumand magnesium of not more than 300 mg and 75 mg respectively per unitdosage based upon the weight of elemental calcium and magnesium in saidoxide and carbonate salts said preparation further characterized ascontaining calcium carbonate present in from 150 mg to 275 mg per unitdosage based on the calcium in said calcium carbonate and the ironsupplement is selected from the group consisting of ferrous fumarate,ferrous gluconate and ferrous sulfate.
 10. A composition according toclaim 9 containing from about 45 mg to about 65 mg of iron supplementbased on the weight of elemental iron.
 11. A multimineral,iron-supplement preparation providing enhanced absorption of iron fromsaid multimineral preparation comprising in combination with saidmineral and iron supplements, oxides and carbonates of calcium andmagnesium of not more than 300 mg and 75 mg respectively per unit dosagebased upon the weight of elemental calcium and magnesium in said oxideand carbonate salts further characterized in that said preparationcontains magnesium oxide present in from 15 mg to 50 mg per unit dosagebased on the weight of magnesium in said magnesium oxide and the ironsupplement is selected from the group consisting of ferrous fumarate,ferrous gluconate and ferrous sulfate.
 12. A composition according toclaim 11 wherein the preparation contains from about 45 to about 65 mgof iron supplement based on elemental iron in said supplement.